Compounds

ABSTRACT

The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof:                    
     in which the group D is selected from a group of formula (A), (B) or (C) below:                    
     in which 
     P is a monocyclic, bicyclic or tricyclic alicyclic ring containing up to 20 carbon atoms in the ring(s); 
     A is a single bond, a C 1-6 alkylene or a C 2-6 alkenylene group; 
     R 1  is halogen, C 1-6 alkyl optionally substituted by one or more fluorine atoms, C 3-6 cycloalkyl, C 1-6 alkoxy, OCF 3 , hydroxy, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkanoyl, amino, alkylamino or dialkylamino, SR 11  where R 11  is hydrogen or C 1-6 alkyl or R 1  is aryl, arylC 1-6 alkyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; 
     n is 0, 1, 2 or 3; and 
     R 2  is hydrogen, C 1-6 alkyl, aryl, arylC 1-6 alkyl or C 3-6 cycloalkyl; or                    
     in which R a  is an alkyl group containing 1 to 20 carbon atoms or is an arylC 1-6 alkyl group, and R b  is hydrogen or C 1-6 alkyl;

This invention relates to novel compounds having pharmacologicalactivity, processes for their preparation, to compositions containingthem and to their use in the treatment of CNS disorders.

EPA 0 021 580 and EPA 0 076 072 describe naphthyl sulphonamidederivatives which are disclosed as having antiarrhythmic activity.European patent application EP 0815861 discloses a series of arylsulphonamide compounds that are said to possess 5HT₆ receptor activityand are useful in the treatment of various CNS disorders. A structurallydistinct class of compounds has now been discovered, which also havebeen found to have 5HT₆ receptor antagonist activity.

The present invention therefore provides, in a first aspect, a compoundof formula (I) or a salt thereof:

in which the group D is selected from a group of formula (A), (B) or (C)below:

in which

P is a monocyclic, bicyclic or tricyclic alicyclic ring containing up to20 carbon atoms in the ring(s);

A is a single bond, a C₁₋₆alkylene or a C₂₋₆alkenylene group;

R¹ is halogen, C₁₋₆alkyl optionally substituted by one or more fluorineatoms, C₃₋₆cycloalkyl, C₁₋₆alkoxy, OCF₃, hydroxy, hydroxyC₁₋₆alkyl,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, C₁₋₆alkanoyl, amino, alkylaminoor dialkylamino, SR¹¹ where R¹¹ is hydrogen or C₁₋₆alkyl or R¹ is aryl,arylC₁₋₆alkyl, a bicyclic heterocyclic ring or is a 5 to 7-memberedheterocyclic ring each containing 1 to 4 heteroatoms selected fromoxygen, nitrogen or sulphur;

n is 0, 1, 2 or 3; and

R² is hydrogen, C₁₋₆alkyl, aryl, arylC₁₋₆alkyl or C₃₋₆cycloalkyl; or

in which R^(a) is an alkyl group containing 1 to 20 carbon atoms or isan arylC₁₋₆alkyl group, and R^(b) is hydrogen or C₁₋₆alkyl;

in which Q is a mono-, bi- or tricyclic group containing a nitrogenheteroatom bonded to the adjacent SO₂ group or Q is a 5-7 memberedheterocyclic ring containing a nitrogen heteroatom bonded to theadjacent SO₂ group and a further heteroatom selected from nitrogen,oxygen or sulphur, and R¹ and n are as defined above;

R³ is a group R⁵ or together with R⁵ forms a group (CH₂)₂O or (CH₂)₃Ooptionally substituted with 1 or more C₁₋₆alkyl groups;

R⁴ is an optionally substituted piperazine ring; and

R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxyoptionally substituted with one or more fluorine atoms, hydroxy,hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, C₁₋₆alkanoyl,trifluoromethyl, or aryl.

Alkyl groups, whether alone or as part of another group, may be straightchain or branched. The term ‘halogen’ is used herein to describe, unlessotherwise stated, a group selected from fluorine, chlorine, bromine oriodine. The term ‘aryl’ is used herein to describe, unless otherwisestated, a group such as phenyl or naphthyl. Such aryl groups may beoptionally substituted by one or more C₁₋₆alkyl or halogen.

Within the Definition of Group D Formula (A)

The group P may be saturated or unsaturated and includes bridged andunbridged bicyclic or tricyclic alicyclic rings, containing saturatedand/or unsaturated rings. Examples of the group P which contain both asaturated and an unsaturated ring include indanyl andtetrahydronaphthyl. With such examples the group A is attached to thegroup P via a carbon atom of the unsaturated ring. When P is amonocyclic ring, suitable examples include cycloalkyl groups containing4 to 10 carbon atoms e.g. cyclopentyl, cyclohexyl or cycloheptyl.Bicyclic and tricyclic rings may contain, for example, 10 to 20 carbonatoms. Examples of bridged bicyclic groups include bicyclo[2.2.1]heptylor born-2-yl and examples of bridged tricyclic groups include adamantyl.Preferably P is cyclohexyl.

When R¹ is a bicyclic heterocyclic ring, suitable examples includebenzothiophene, indole, benzimidazole, quinoline or isoquinoline.Suitable 5 to 7-membered heterocyclic rings include thienyl, furyl,pyrrolyl, triazolyl, imidazolyl, oxazoly, thiazolyl, oxadiazolyl,isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyland pyrazinyl. The heterocyclic rings can be linked to the remainder ofthe molecule via any suitable carbon atom or, when present, a nitrogenatom. Preferably R¹ is a C₁₋₆alkyl group such as methyl or ethyl.Preferably n is 0, 1 or 2.

When R² is a C₃₋₆cycloalkyl group a preferred example is cyclohexyl.Preferably R² is hydrogen or a C₁₋₆alkyl group such as methyl, ethyl orisopropyl.

Suitably A is a single bond, a methylene or ethylene group or a—CH═CH—group. Preferably A is a single bond or methylene.

Within the Definition of Group D Formula (B)

The alkyl group R^(a) may be straight chain or branched. PreferablyR^(a) represents a C₁₋₈alkyl group.

Preferably R^(b) is hydrogen.

Within the Definition of Group D Formula (C)

When Q is a mono-, bi- or tricyclic group containing a single nitrogenheteroatom, suitable examples may be saturated or unsaturated includingpartially unsaturated groups for example bicyclic groups in which onering is saturated and the other is unsaturated. Monocyclic groupspreferably contain 4 to 8 atoms in the ring, advantageously six atoms, apreferred example of such a monocyclic group being piperidine. Bicyclicgroups, which may be bridged or unbridged, preferably contain 8 to 12atoms in the rings, advantageously 10 atoms, preferred examples of suchbicyclic groups being decahydroquinoline or decahydroisoquinoline.Tricyclic groups, which may be bridged or unbridged, preferably contain6 to 14 atoms in the rings. When Q is a 5-7 membered heterocyclic ringcontaining a further heteroatom, suitable examples include piperazinyl,morpholinyl or thiomorpholinyl.

When R¹ is a bicyclic heterocyclic ring or a 5-7 membered heterocylicring suitable examples include those listed for R¹ within the definitionof formula (A). Preferably R¹ is a C₁₋₆alkyl group such as methyl orethyl or an arylC₁₋₆alkyl group such as benzyl. Preferably n is 0, 1 or2.

R³ is a group R⁵ or together with R⁵ forms a group (CH₂)₂O or (CH₂)₃O.It will be appreciated that when R³/R⁵ groups are linked together thetwo groups must be attached to adjacent carbon atoms of the phenyl ring.Preferably R³ is a group R⁵, in particular hydrogen.

Preferably R⁴ is meta with respect to the SO₂ group. Optionalsubstituents for the piperazine ring, which can be present on carbonand/or nitrogen atoms, include C₁₋₆alkyl, in particular methyl. Mostpreferably R⁴ is unsubstituted piperazine.

Suitably R⁵ is C₁₋₆alkoxy. Preferably R⁵ is a methoxy group with a pararelationship with respect to the SO₂ group.

Particular compounds of the invention include:

N-Cyclohexyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-Indan-1-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-Bicyclo[2.2.1]hept-2-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-Adamantan-1-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-Cycloheptyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-Cyclohexyl-4-methoxy-N-methyl-3-piperazin-1-ylbenzenesulfonamide,

N-Adamantan-2-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-Cyclopentyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

1-[5-(4-Benzylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine,

N-Hexyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-Indan-2-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

1-[5-(3,3-Dimethylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine,

1-[5-(2-Ethylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine,

4-Methoxy-N-(1-methylbutyl)-3-piperazin-1-ylbenzenesulfonamide,

N-tert-Butyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

(R)-4-Methoxy-3-piperazin-1-yl-N-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-benzenesulfonamide,

N-(4-tert-Butylcyclohexyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

4-Methoxy-N-(2-methylcyclohexyl)-3-piperazin-1-ylbenzenesulfonamide,

4-Methoxy-N-(3-methylcyclohexyl)-3-piperazin-1-ylbenzenesulfonamide,

4-Methoxy-N-(4-methylcyclohexyl)-3-piperazin-1-ylbenzenesulfonamide,

N-(2,3-Dimethylcyclohexyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

1-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)decahydroquinoline,

2-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)decahydroisoquinoline,

N-[2-(4-Fluoro-phenyl)-1,1-dimethyl-ethyl]-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(1,1-Dimethyl-propyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-Cyclohexyl-4-methoxy-N-phenyl-3-piperazin-1-yl-benzenesulfonamide,

N,N-Dicyclohexyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(1-(R)-Cyclohexyl-ethyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(1-(S)-Cyclohexyl-ethyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-Cyclohexyl-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-Cyclohexyl-N-isopropyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

4-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)morpholine,

4-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)thiomorpholine,

4-Methoxy-3-piperazin-1-yl-N-(1,1,3,3-tetramethylbutyl)benzenesulfonamidean pharmaceutically acceptable salts thereof.

The compounds of the formula (I) can form acid addition salts withacids, such as conventional pharmaceutically acceptable acids, forexample maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.

Compounds of formula (I) may also form solvates such as hydrates, andthe invention also extends to these forms. When referred to herein, itis understood that the term ‘compound of formula (I)’ also includesthese forms.

Certain compounds of formula (I) are capable of existing instereoisomeric forms including diastereomers and enantiomers and theinvention extends to each of these stereoisomeric forms and to mixturesthereof including racemates. The different stereoisomeric forms may beseparated one from the other by the usual methods, or any given isomermay be obtained by stereospecific or asymmetric synthesis. The inventionalso extends to any tautomeric forms and mixtures thereof.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises the coupling of a compound of formula (II):

D—H  (II)

in which D is as defined in formula (I) or protected derivatives thereofwith a compound of formula (III):

in which R³, R⁴ and R⁵ are as defined in formula (I) or protectedderivatives thereof and L is a leaving group and optionally thereafter:

removing any protecting groups,

forming a pharmaceutically acceptable salt.

Suitable leaving groups include halogen, in particular chloro. Thereaction of a compounds of formulae (II) and (III) is carried out bymixing the two reagents together, optionally in an inert solvent such asdichloromethane with or without the addition of a suitable base such astriethylamine.

Those skilled in the art will appreciate that it may be necessary toprotect certain groups. Suitable protecting groups and methods for theirattachment and removal are conventional in the art of organic chemistry,such as those described in Greene T. W. ‘Protective groups in organicsynthesis’ New York, Wiley (1981).

Compounds of formulae (II) and (III) are commercially available or maybe prepared according to known methods or analogous to known methods.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

Compounds of formula (I) and their pharmaceutically acceptable saltshave 5HT₆ receptor antagonist activity and are believed to be ofpotential use in the treatment of certain CNS disorders such as anxiety,depression, epilepsy, obsessive compulsive disorders, migraine,cognitive memory disorders e.g. Alzheimers disease, Parkinson' Disease,ADHD (Attention Deficit Disorder/Hyperactivity Syndrome), sleepdisorders (including disturbances of Circadian rhythym), feedingdisorders such as anorexia and bulimia, panic attacks, withdrawal fromdrug abuse such as cocaine, ethanol, nicotine and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injury such as hydrocephalus. Compounds of the invention are alsoexpected to be of use in the treatment of certain GI (gastrointestinal)disorders such as IBS (Irritable Bowel Syndrome).

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance, in particular in the treatment or prophylaxis of the abovedisorders.

The invention further provides a method of treatment or prophylaxis ofthe above disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment or prophylaxis of theabove disorders.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusable solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unitdoses may be administered more than once a day, for example two or threea day, so that the total daily dosage is in the range of about 0.5 to100 mg; and such therapy may extend for a number of weeks or months.

When administered in accordance with the invention, no unacceptabletoxicological effects are expected with the compounds of the invention.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

Description 1

2-(4-Trichloroacetylpiperazin-1-yl) anisole (D1)

A solution of 1-(2-methoxyphenyl) piperazine (7.0 g) in dichloromethane(30 ml) was added over 15 minutes to a stirred solution oftrichloroacetyl chloride (4.06 ml) in dichloromethane (40 ml) at roomtemperature under argon. Diisopropylethylamine (5.95 ml) was then addedand the whole was stirred for 18 hours. The reaction mixture was washedwith water (2×100 ml), dried (Na₂SO4) and concentrated to give the titlecompound (D1) as an oil (11.2 g, 91%), MH⁺337/339.

Description 2

3-(4-Trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride(D2)

A solution of 2-(4-trichloroacetylpiperazin-1-yl) anisole (D1) (10 g) indichloromethane (115 ml) was added over 0.3 h to ice-cooledchlorosulfonic acid (52 ml). After 0.5 h at 0° C. then 1 hour at ambienttemperature, the solution was poured onto a mixture of ice-water (500 g)and dichloromethane (500 ml) with rapid stirring. The layers wereseparated and the organic phase was washed with water (2×800 ml), dried(MgSO₄) and concentrated to give the title compound (D2) as a foam (6.0g, 46%), MH⁺ 435/437.

EXAMPLE 1 N-Cyclohexyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamidehydrochloride (E1)

A solution of cyclohexylamine (91 mg) in dichloromethane (1 ml) wasadded slowly to a stirred solution of3-(4-trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride(D2) (200 mg) in dichloromethane (2 ml). The mixture was stirredovernight then washed with 1M HCl (4 ml) and water (4 ml), dried andconcentrated to a solid. The solid was dissolved in tetrahydrofuran or1,4-dioxane (5 ml) and to the solution was added 0.15M potassiumhydroxide solution (5 ml) and the whole stirred at ambient temperaturefor 8 hours. The solution was concentrated to remove the organic solventand the aqueous residue was extracted with dichloromethane (2×20 ml).The combined extracts were dried, acidified with 1M ethereal hydrogenchloride (1 ml), concentrated to an oil and stirred with acetone/diethylether to afford the title compound (E1) (28 mg, 21%). δH (250 MHz,d6-DMSO) 1.10 (5H, br, s), 1.56 (5H, br, s), 2.86 (1H, br, s), 3.21 (8H,br, s), 3.87 (3H, s), 7.13 (1H, d, J=8.0 Hz), 7.33 (1H, s), 7.46-7.52(2H, m), 9.19 (2H, br, s), MH+354.

EXAMPLE 2 N-Indan-1-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamidehydrochloride (E2)

To a stirred solution of3-(4-Trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride(0.46 mmol) in dichloromethane (2 ml) was added a solution of amine (1mmol) in dichloromethane (1 ml). The mixture was stirred at ambienttemperature overnight, then dichloromethane (4 ml) was added and theresulting solution was washed with 1M HCl (4 ml) and water (4 ml), dried(Na₂SO₄) and concentrated to a solid. The solid was dissolved in1,4-dioxane (9 ml) or 1,4-dioxane:tetrahydrofurane (5:4, v/v, 9 ml), 1Maqueous potassium hydroxide (1 ml) was added and the reaction wasstirred at ambient temperature for 17 hours. The solvent was partiallyremoved, water was added (5 ml) and the solution was extracted withdichloromethane (2×10 ml). The combined extracts were dried (Na₂SO₄) andevaporated to dryness. The residue was redissolved in dichloromethane (2ml), acidified with 1M hydrogen chloride in diethyl ether (1 ml) andconcentrated to afford the title compound as a solid (E2) (177 mg, 91%),MH⁺ 388.

The following compounds were prepared by a similar method to thatdescribed in Example 2 using the appropriate amine. All amines areeither commercially available or can be prepared according to literatureprocedures.

Compound MH⁺ N-Bicyclo[2.2.1]hept-2-yl-4-methoxy-3-piperazin-1- 366ylbenzenesulfonamide (E3) N-Adamantan-1-yl-4-methoxy-3-piperazin-1- 406ylbenzenesulfonamide (E4)N-Cycloheptyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 368 (E5)N-Cyclohexyl-4-methoxy-N-methyl-3-piperazin-1- 368ylbenzenesulfonamide(E6) N-Adamantan-2-yl-4-methoxy-3-piperazin-1- 406ylbenzenesulfonamide (E7)N-Cyclopentyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 340 (E8)1-[5-(4-Benzylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine 430(E9) N-Hexyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (E10) 356N-Indan-2-yl-4-methoxy-3-piperazin-1-ylbenzensulfonamide 388 (E11)1-[5-(3,3-Dimethylpiperidine-1-sulfonyl)]-2- 368methoxyphenyl]piperazine (E12)1-[5-(2-Ethylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine 368(E13) 4-Methoxy-N-(1-methylbutyl)-3-piperazin-1-ylbenzenesulfonamide 342(E14) N-tert-Butyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (E15)328 (R)-4-Methoxy-3-piperazin-1-yl-N-(1,7,7- 408trimethylbicyclo[2.2.1]hept-2-yl)-benzenesulfonamide (E16)N-(4-tert-Butylcyclohexyl)-4-methoxy-3-piperazin-1- 410ylbenzenesulfonamide (E17)4-Methoxy-N-(2-methylcyclohexyl)-3-piperazin-1- 368 ylbenzenesulfonamide(E18) 4-Methoxy-N-(3-methylcyclohexyl)-3-piperazin-1- 368ylbenzenesulfonamide (E19)4-Methoxy-N-(4-methylcyclohexyl)-3-piperazin-1- 368 ylbenzenesulfonamide(E20) N-(2,3-Dimethylcyclohexyl)-4-methoxy-3-piperazin-1- 382ylbenzenesulfonamide (E21)1-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)decahydroquinoline 394(E22) 2-(4-Methoxy-3-piperazin-1- 394ylbenzenesulfonyl)decahydroisoquinoline (E23)N-[2-(4-Fluoro-phenyl)-1,1-dimethyl-ethyl]-4-methoxy-3- 422piperazin-1-yl-benzenesulfonamide (E24)N-(1,1-Dimethyl-propyl)4-methoxy-3-piperazin-1-yl- 342benzenesulfonamide (E25)N-Cyclohexyl-4-methoxy-N-phenyl-3-piperazin-1-yl- 430 benzenesulfonamide(E26) N,N-Dicyclohexyl-4-methoxy-3-piperazin-1-yl- 436benzenesulfonamide (E27)N-(1-(R)-Cyclohexyl-ethyl)-4-methoxy-3-piperazin-1-yl- 382benzenesulfonamide (E28)N-(1-(S)-Cyclohexyl-ethyl)-4-methoxy-3-piperazin-1-yl- 382benzenesulfonamide (E29)N-Cyclohexyl-N-ethyl-4-methoxy-3-piperazin-1-yl- 382 benzenesulfonamide(E30) N-Cyclohexyl-N-isopropyl-4-methoxy-3-piperazin-1-yl- 396benzenesulfonamide (E31)4-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)morpholine (E32) 3424-(4-Methoxy-3-piperazin-1-ylbenzensulfonyl)thiomorpholine 358 (E33)4-Methoxy-3-piperazin-1-yl-N-(1,1,3,3-tetramethylbutyl) 384benzenesulfonamide (E34)

Pharmacological Data

Compounds can be tested following the procedures outlined in WO98/27081. All compounds tested showed good affinity for the 5-HT₆receptor, having pKi values 7.4-8.8 at human cloned 5-HT₆ receptors.Particularly preferred compounds demonstrated pKi>7.9 and >100 foldselectivity. Examples of such compounds include:

E1, E3-7, E17-22, E27, E30-31.

What is claimed is:
 1. A compound of formula (I) or a salt thereof:

in which the group D is selected from a group of formula (A), (B) or (C) below:

in which P is a monocyclic alicyclic ring containing 4-10 carbon atoms; A is a single bond, a C₁₋₆alkylene or a C₂₋₆alkenylene group; R¹ is halogen, C₁₋₆alkyl optionally substituted by one or more fluorine atoms, C₃₋₆cycloalkyl, C₁₋₆alkoxy, OCF₃, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, C₁₋₆alkanoyl, amino, alkylamino or dialkylamino, SR¹¹ where R¹¹ is hydrogen or C₁₋₆alkyl or R¹ is aryl, or arylC₁₋₆alkyl; n is 0, 1, 2 or 3; and R² is hydrogen, C₁₋₆alkyl, aryl, arylC₁₋₆alkyl or C₃₋₆cycloalkyl; or

in which R^(a) is an alkyl group containing 1 to 20 carbon atoms or is an arylC₁₋₆alkyl group, and R^(b) is hydrogen; or

in which Q is a monocyclic group containing a nitrogen heteroatom bonded to the adjacent SO₂ group or Q is a 5 or 6-membered heterocyclic ring containing a nitrogen heteroatom bonded to the adjacent SO₂ group and a further heteroatom selected from nitrogen, oxygen or sulphur, and R¹ and n are as defined above; R³ is a group R⁵; R⁴ is a piperazine ring optionally substituted by C₁₋₆ alkyl; R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy optionally substituted with one or more fluorine atoms, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, C₁₋₆alkanoyl or trifluoromethyl.
 2. A compound according to claim 1 in which P is cyclohexyl.
 3. A compound according to claim 1 in which Q is piperdine.
 4. A compound according to claim 3 in which R¹ is C₁₋₆alkyl.
 5. A compound according to claim 4 in which R⁴ is an unsubstituted piperazine ring.
 6. A compound according to claim 5 in which R⁵ is methoxy.
 7. A compound according to claim 1 which is selected from the group consisting of: N-Cyclohexyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-Cycloheptyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-Cyclohexyl-4-methoxy-N-methyl-3-piperazin-1-ylbenzenesulfonamide, N-Cyclopentyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 1-[5-(4-Benzylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine, N-Hexyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 1-[5-(3,3-Dimethylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine, 1-[5-(2-Ethylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine, 4-Methoxy-N-(1-methylbutyl)-3-piperazin-1-ylbenzenesulfonamide, N-tert-Butyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(4-tert-Butylcyclohexyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 4-Methoxy-N-(2-methylcyclohexyl)-3-piperazin-1-ylbenzenesulfonamide, 4-Methoxy-N-(3-methylcyclohexyl)-3-piperazin-1-ylbenzenesulfonamide, 4-Methoxy-N-(4-methylcyclohexyl)-3-piperazin-1-ylbenzenesulfonamide, N-(2,3-Dimethylcyclohexyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-[2-(4-Fluoro-phenyl)-1,1-dimethyl-ethyl]-4-methoxy-3-piperazin-1-yl-benzenesulfonamide, N-(1,1-Dimethyl-propyl)4-methoxy-3-piperazin-1-yl-benzenesulfonamide, N-Cyclohexyl-4-methoxy-N-phenyl-3-piperazin-1-yl-benzenesulfonamide, N,N-Dicyclohexyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide, N-(1-(R)-Cyclohexyl-ethyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide, N-(1-(S)-Cyclohexyl-ethyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide, N-Cyclohexyl-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide, N-Cyclohexyl-N-isopropyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide, 4-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)morpholine, 4-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)thiomorpholine, and 4-Methoxy-3-piperazin-1-yl-N-(1,1,3,3,-tetramethylbutyl)benzenesulfonamide and pharmaceutically acceptable salts thereof.
 8. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises the coupling of a compound of formula (II): D—H  (II) in which D is as defined in formula (I) or protected derivatives thereof with a compound of formula (III):

in which R³, R⁴ and R⁵ are as defined in formula (I) or protected derivatives thereof and L is a leaving group by mixing the two reagents together with or without an inert solvent with or without the addition of a suitable base, and optionally thereafter removing any protecting groups; forming a pharmaceutically acceptable salt.
 9. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.
 10. A method of treating Alzheimer's disease, schizophrenia or depression comprising administering to a patient in need of treatment a safe and therapeutically effective amount of a compound according to claim
 1. 